Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNAs carrying premature translation termination codons. Generally, NMD is elicited if translation terminates >50-54 nucleotides (nt) upstream of an exon-exon junction. We have previously reported that human beta-globin mRNAs carrying 5'-proximal nonsense mutations (e.g., beta15) accumulate to normal levels, suggesting an exception to the "50-54-nt boundary rule." In the present report, we demonstrate that the strength of the UPF1-dependent NMD of mutant beta-globin mRNAs is specifically determined by the proximity of the nonsense codon to the initiation AUG. This conclusion is supported by a parallel effect of the short ORF size on NMD of nonsense-containing alpha-globin mRNAs. To determine whether the short-ORF effect on NMD response is conserved in heterologous transcripts, we assessed its effects on a set of beta-globin/triosephosphate isomerase (TPI) hybrid mRNAs and on the TPI mRNA. Our data support the conclusion that nonsense mutations resulting in a short ORF are able to circumvent the full activity of the canonical UPF1-dependent NMD pathway.